上海交通大学：《药剂学》教学资源（课件讲义）12targeted-oriented drug delivery-2

Target-Oriented Drug Delivery 2

Target-Oriented Drug Delivery 2

Three approaches for drug targeting Biological active agents that are both potent and specific ·The prodrug approach Targeted drug delivery systems

Three approaches for drug targeting • Biological active agents that are both potent and specific • The prodrug approach • Targeted drug delivery systems

The Gleevec miracle Blocks the activity of the BCR-ABL enzyme that ADP ATP causes the cells to become PO, cancerous and multiply TYR bcr-abl bcr-abl tyrosine Sub- tyrosine Sub- Has ability to distinguish kinase strate kinase strate between carcinomic WBC and normal WBC Altered cellular adhesion Ahered cellular adhesion Abnormal prolileraton Abnormal peolferaton Inhibon of apootosis nbition of apoptosis Effective in gastrointestinal CML stromal tumor(GIST),and acute lymphocytic leukemia The Oncologist 2001,;6:233-238 June 2001

The Gleevec miracle • Blocks the activity of the BCR-ABL enzyme that causes the cells to become cancerous and multiply • Has ability to distinguish between carcinomic WBC and normal WBC • Effective in gastrointestinal stromal tumor (GIST), and acute lymphocytic leukemia The Oncologist 2001;6:233-238 June 2001

Philadelphia Chromosome? ·A shortened Normal Translocation Chromosome Chromosome chromosome 22 90+ Normal resulting from the Chromosome Philadelphia 22 Chromosome translocation between chromosome 9 and chromosome 22 c-ab ·Produces BCR-ABL oncogene http://www.hhmi.org/bulletin/dec2001/gleevec/

Philadelphia Chromosome? • A shortened chromosome 22 resulting from the translocation between chromosome 9 and chromosome 22 • Produces BCR-ABL oncogene http://www.hhmi.org/bulletin/dec2001/gleevec/

Of the 54 patients in the more advanced stage, 98%of the patients reached a hematologic response Recent studies reported in New England Journal of Medicine (NEJM)in 2003: - Of 1,106 patients,74%of newly diagnosed patients in the chronic phase treated with Gleevec achieved a complete cytogenic response,compared to 8%of those treated with interferon and cytosine arabinoside. - 92%of the patients taking Gleevec had an improved overall progression-free survival

• Of the 54 patients in the more advanced stage, 98% of the patients reached a hematologic response • Recent studies reported in New England Journal of Medicine (NEJM) in 2003: – Of 1,106 patients, 74% of newly diagnosed patients in the chronic phase treated with Gleevec achieved a complete cytogenic response, compared to 8% of those treated with interferon and cytosine arabinoside. – 92% of the patients taking Gleevec had an improved overall progression-free survival

EGFR Signal Transduction in Tumor Cells R R R Gene iranseription and cell cycle progression evelin D1 Jun Fos

myc cyclin D1 Jun Fos R R R R EGFR Signal Transduction in Tumor Cells K K K K Gene transcription and cell cycle progression Gene transcription and cell cycle progression

EGFR Signal Transduction in Tumor Cells R R RAS RAF PI3-K Sos GRB2 MEK AKT MAPK Gene iran. cion and cell cy以 yression ao evelin D1 Jun Fos tion ls

Angiogenesis Metastasis myc cyclin D1 Jun Fos R R EGFR Signal Transduction in Tumor Cells K K R K R K Gene transcription and cell cycle progression Gene transcription and cell cycle progression MAPK MEK RAS RAF SOS GRB2 Proliferation PI3-K AKT Inhibition of apoptosis P P P P P P

IRESSA® ICso (uM) Selective enzyme inhibition -EGFR (ErbB-1): 0.033 Other cellular kinases >3 EGFR autophosphorylation <1 inhibition in tumor cell lines Tumor cell growth inhibition -EGF stimulated 0.054 Basal 8.8

IRESSA® IC50 (µM) • Selective enzyme inhibition – EGFR (ErbB-1): 0.033 – Other cellular kinases > 3 • EGFR autophosphorylation < 1 inhibition in tumor cell lines • Tumor cell growth inhibition – EGF stimulated 0.054 – Basal 8.8

IRESSAR Inhibits Growth of A549 Xenograft Tumors (NSCLC) IRESSA 200 mg/kg,po days 10-72 IRESSA 200 mg/kg,po days 10-30 0.8 AVehicle 0.7 0.6 0.5 0.4 0.3 0 0.1 8。"◇。.0" 0 0 20 40 60 80 Day

0 20 40 60 80 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 Day Mean tumor volume, cm3 IRESSA ® Inhibits Growth of A549 Xenograft Tumors (NSCLC) IRESSA 200 mg/kg, po days 10 - 72 IRESSA 200 mg/kg, po days 10 - 30 Vehicle

Herceptin (trastuzumab) is a chimeric (95% human)monoclonal antibody directed Extracellular domain 1632 amind acids) against the extra- Ligand-binding site cellular domain of the HER-2/neu receptor Intracellular domain (580 amino acids) Cetuximab/Erbitux/C- Tyrosine kinase activity 225:Anti-EGFR

• Herceptin (trastuzumab) is a chimeric (95% human) monoclonal antibody directed against the extra￾cellular domain of the HER-2/neu receptor • Cetuximab/Erbitux/C- 225: Anti-EGFR Extracellular domain (632 amino acids) Ligand-binding site Transmembrane domain (22 amino acids) Intracellular domain (580 amino acids) Tyrosine kinase activity